High-risk neuroblastoma accounts for the second most pediatric cancer deaths. Amplification of MYCN accounts for many of these cases, while other less-understood mechanisms account for non-MYCN amplified high-risk neuroblastoma. We have recently demonstrated that amplified MYCN is synthetic lethal to the FDA-approved BCL-2 inhibitor, venetoclax (ABT-199). Herein, we uncover several rational implementations of venetoclax in MYCN-amplified neuroblastoma therapy and aim to preclinically test them. In addition, we provide rational and evidence that venetoclax can be effective in combination in high-risk MYCN-wild-type neuroblastoma, based on a newly discovered apoptotic block in these cancers. Lastly, through high-throughput drug screening, we uncover a novel class of drug that has potent, specific and broad activity across neuroblastoma, and combines with venetoclax to eliminate virtually all neuroblastoma cells. Objectives: High-risk neuroblastoma is refractory to current treatment regimens. By studying the molecular vulnerabilities of these cancers, we propose several new promising treatments to specifically combat subsets of high-risk neuroblastoma, with the overall goal to ready these for clinical testing. Specific Aim #1. Determine anti-cancer activity of standard-of-care chemotherapy and venetoclax against molecularly heterogeneous neuroblastoma cell lines and animal models. Here, we will evaluate the efficacy of venetoclax with the standard-of-care chemotherapy in multiple mouse models of neuroblastoma. Specific Aim 2: Characterize the efficacy and safety of venetoclax/ MDM2 inhibitor combination therapy in p53 wild-type neuroblastoma in cell lines and animal models. Here, we will determine the mechanisms of in vitro efficacy of MDM2 inhibitors in combination with venetoclax in p53 wild-type neuroblastoma, and define vivo efficacy and safety. Specific Aim 3: Characterize the efficacy and safety of H3K27me3 inhibition alone and in combination with venetoclax. We have identified a novel class of drug with potent and specific activity in neuroblastoma. We will further define the mechanism(s) of this sensitivity in vitro and in vivo. Study Design/Methods: Utilizing an innovative pharmacogenomics approach that has uncovered several novel targeted therapies that have reached or are headed to clinical trials, we will evaluate other novel drugs for efficacy in neuroblastoma in combination with venetoclax. Using multiple in vitro models of neuroblastoma, we will study the relationship between particular drug vulnerabilities and the molecular underpinnings of that sensitivity. Lastly, we will rigorously evaluate preclinical efficacy and safety of our novel targeted therapy combinations in multiple and diverse animal models of neuroblastoma.